I. Field of the Invention
The invention is directed generally to a catheter or other invasive vascular navigating device intended to enable deployment of biologically active materials. More particularly, the invention involves a vascular catheter system for the electrical charge mediated deployment of biologically active materials into specific segments of living blood vessels. This includes transplanting biologically functional autologous vascular endothelium into blood vessels whose endothelium and subendothelial structures have been damaged as well as altering endothelial and subendothelial biology by the electrical application of metabolic activators or inhibitors.
II. Description of the Related Art
Coronary artery disease is a significant problem throughout the world, and it is among the major consequences of injured endothelial cells. If left to its natural history, coronary artery disease invariably leads to death. The past two decades of cardiovascular research have resulted in the birth and growth of interventional cardiovascular procedures which have made a major impact on the morbidity and mortality of patients with this disease. According to 1992 statistics, an estimated 750,000 patients with coronary artery disease will undergo coronary artery balloon angioplasty or atherectomy to open a blocked artery. However, since the first percutaneous transluminal coronary angioplasty (PTCA) performed in 1977 by Andreas Gruentzig, cardiovascular interventionalists have been witness to generally disappointing long-term results with respect to the post-PTCA vessel patency. Approximately 30% to 50% of the treated patients will have recurrence (restenosis) of their arterial obstructions and will require further angioplasty treatment or open heart surgery.
Restenosis of angioplasted vascular segments has prompted a multifaceted, international research campaign attempt to improve post-PTCA long-term vessel patency. Much of this research has been focused on improving balloon catheter designs, understanding lesion characteristics, improving patient selection for angioplasty procedures and elucidating the pathophysiology of restenosis.
A major cause of this restenosis is the absence or disruption of the normal cells (endothelial cells) that line the internal surface of a normal arterial segment. This cell lining, known as vascular endothelium, is often disrupted or destroyed by the atherosclerotic disease process and by the previously mentioned stenosis reduction or removal procedures. Maintaining vascular endothelial integrity is important as it performs a variety of vital functions necessary to support life. These functions are contingent upon the presence of morphologically intact and biologically functional endothelial cells and their intimate association with subendothelial structures. Disruption of the framework of this biological system causes the endothelial cells to become dysfunctional, and it is this critical event which sets the stage for the onset or recurrence of vascular disease and its devastating progression.
In this regard, vascular smooth muscle cell proliferation appears to be a pivotal event in the pathology of restenosis. Smooth muscle cell proliferation is, in part, triggered by the mitogenic properties of platelet-derived growth factor (PDGF). However, it is generally believed that more than one mitogenic activator is responsible for this process. There is further evidence suggesting that endothelial cells help to modulate vascular smooth muscle cell biology and that when endothelial cells become dysfunctional, vascular smooth muscle cells favor a synthetic (proliferative) state. Further discussion is provided by, for example, Haudenschild, C. C., "Growth control of endothelial cells in atherogenesis and tumor angiogenesis", Advances in Microcirculation, 9 (1980) 226-251; Ross, R., "The pathogenesis of atherosclerosis", in Braunwald, E. (ed): Heart Disease, 3d Edition, Saunders WB, 1988, 1135-1152; Ross, R. and J. Glomset, "Atherosclerosis and arterial smooth muscle cell", Science 180 (1973) 1332.
Since PTCA traumatizes vascular endothelium and subendothelial structures, it triggers a cascade of biological events which may lead to smooth muscle cell proliferation. To a great extent, this PDGF-mediated process may be held in check by platelet inhibitors and heparin sulfate. However, because PDGF, and other smooth muscle mitogens, are not only released by platelets, but also by dysfunctional endothelial cells, uncontrolled smooth muscle cell proliferation can still occur.
Vascular endothelial cells grow in an obligate monolayer attached by tight junctions and gap junctions. Maintenance of this structural design is essential for the normal biological function of endothelial cells and this framework is, in part, accomplished through a type IV collagen matrix upon which endothelial cells reside. If endothelial cells are unable to adhere to a given surface, they become nonviable. In vivo placement of endothelial cells upon this collagen matrix is inherently problematic because laminar flow produces forces of shear stress resulting in an intravascular environment which is not conducive for endothelial cell attachment. However, freshly endarterectomized aortas incubated in vitro, in a low flow, low pressure environment with homologous aortic endothelial cells for 20 minutes result in rapid endothelial cell attachment, as reported by Schneider et al, "Confluent durable endothelialization of endarterectomized baboon aorta by early attachment of cultured endothelial cells, J Vasc Surg 11:365-372, 1990. In vivo exposure of these attached cells to laminar blood flow and pressure for one hour yields a thromboresistant, confluent and durable monolayer. It has also been shown that in vitro seeding of genetically engineered endothelial cells onto catheter mounted stainless steel vascular stents remain not only adherent but also viable after stent expansion and exposure to in vitro pulsatile flow (Flugelman et al, "Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to flow in vitro", Circ Res 70:348-354, 1992) Finally, endothelial cells freshly obtained from human fat and acutely seeded in vitro onto plasma coated dacron grafts for one hour, remain adherent and form confluent monolayers when exposed to flow for two hours at a shear stress of 0 to 80 dynes/cm.sup.2 (Jarrell et al, "Use of freshly isolated capillary endothelial cells for the immediate establishment of a monolayer on a vascular graft at surgery, Surgery 100(2):392-399, 1986).
Since endothelial cells contain much of the biological armamentarium necessary to orchestrate the molecular events required to maintain a thromboresistant and homeostatic vascular milieu, it follows that if a device were available to quickly reestablish a normal endothelial monolayer immediately following angioplasty or atherectomy, the incidence of restenosis could be significantly reduced and possibly eliminated. The high flow velocities of the intravascular hemodynamic environment, however, technically limits in vivo application of endothelial seeding onto denuded intravascular surfaces.
Invasive implant devices including catheters have been proposed which deliver an electric charge to remote areas of a patient's body. One such catheter device intended for relatively long-term use has been devised that applies a unidirectional negative charge to discourage microbial growth at the implant interface surface. This is shown in UK patent application GB 2 219 510. A PCT application WO 85/02779 discloses a catheter for treating tumors which delivers a high frequency heat producing current to the tumor tissue.
Other catheter devices are known that employ a plurality of spaced fluid inflated balloon devices for isolating and treating segments of blood vessels and other body passages such as trachea and urethra. Examples of such devices which also allow bypass flow around an isolated segment are found in Weikl et al (U.S. Pat. No. 4,610,662) and Baran et al (U.S. Pat. No. 4,423,725). A further multiple balloon device is illustrated in Wolinsky (U.S. Pat. No. 4,636,195).
The present invention addresses this problem by providing a new device which includes a system for deployment of biologically active materials (endothelial cells) into specific segments of living blood vessels to be reseeded with new, autologously derived endothelial cells. The invention also provides for iontophoretic delivery of biologic/pharmacologic agents into these specific vascular segments. One design aspect of the device provides for significantly diminished blood flow in the specific vascular segments of interest for a time long enough, for example, to allow cultured endothelial cells to adhere to the vascular surface. This is accomplished by providing an integral bypass system to simultaneously re-establish blood flow beyond the isolated area.